The present invention relates to formulations and methods useful in reducing serum bilirubin, and thus the incidence of infant jaundice, in breast feeding babies. More particularly, it relates to the use of L-aspartic acid and/or L-malic acid in formulas and supplements used in addition to breast milk.
Bilirubin is the red bile pigment formed during the catabolism of certain compounds such as hemoglobin. Human infants produce more bilirubin per unit of body weight than do adults because of greater red blood cell mass and shorter red blood cell life span. Bilirubin is poorly soluble in water and requires conjugation for excretion from the body.
Bilirubin is conjugated with glucuronic acid within the endoplasmic reticulum of the hepatocyte. Bilirubin conjugates in the intestine can act as a substrate for either bacterial or endogenous tissue xcex2-glucuronidase. This enzyme hydrolyzes glucuronic acid from bilirubin glucuronide. The resulting unconjugated bilirubin produced is more rapidly absorbed from the intestine. This intestinal absorption of free bilirubin results in increased serum bilirubin levels in some neonates, which has been associated with infant jaundice.
More than thirty years ago aspartic acid was regarded as a possible therapy for neonatal jaundice in the belief that aspartic acid administration would increase uridine diphosphoglucuronic acid (UDPGA) concentration and resultant hepatic bilirubin conjugation. See S. Matsuda et al., 90 Tohoku J. Exp. Med. 133-136 (1966)(aspartic acid, 200 mg/day, was given to full-term newborn Japanese infants). The author of this article has indicated that the diet was formula rather than breast feeding.
See also A. Saito et al., 27 Shohni-ka-Shinryo 124 (1964) (serum bilirubin level decreased by administration of aspartic acid in some cases of hyperbilirubinemia); G. Kohno et al., 16 Shohni-ka-Rinsho 565-569 (1963) (a premature infant with neonatal hyperbilirubinemia had serum bilirubin level lowered by aspartic acid).
A subsequent Scottish double-blind study of pre-term formula-fed infants found no effect of aspartic acid on serum bilirubin concentrations when the aspartic acid was given for each of the first six days of life. See D. Gray et al., 46 Arch. Dis. Child. 123-124 (1971). This negative result marked the end of the period of investigations regarding the effects of aspartic acid on serum bilirubin levels.
It has been previously published that infants fed a certain type of casein hydrolysate formula (yet not certain other types of formula) had significantly lower levels of infant jaundice. It had been proposed that this is due to inhibition of xcex2-glucuronidase by the formula. See G. Gourley, et al., 103 Gastroenterology 660-667 (1992); G. Gourley, et al., 25 J. Ped. Gast. and Nutr. 267-272 (1997); and G. Gourley, 44 Advances in Pediatrics 173-229, Chapter 6 (1997). The disclosure of these publications and of all other publications referred to herein are incorporated by reference as if fully set forth herein.
Pediatricians recommend breast feeding as the best way to feed neonates. However, notwithstanding the many benefits of breast feeding, it has been associated with increased levels of neonatal jaundice. Neonatal jaundice is mostly likely to occur during the first month (especially the first week) after a baby has been born. This is precisely the time that most mothers are attempting to breast feed. Thus, it is desirable to find a supplement that can be added to the breast milk itself which reduces the incidence of infant jaundice.
Further, even where a mother is willing to feed a formula (e.g. a casein hydrolysate based formula such as Nutramigen(copyright)) it is desirable to be able to optimize the ability of such formulas to reduce the incidence of neonate jaundice when initial signs of such jaundice appear.
Moreover, it is desirable to find ways to reduce the cost of adding supplements to the neonatal diet.
Thus, it can be seen that a need still exists for improved infant formulas and supplements.
The inventors have discovered that L-aspartic acid and L-malic acid significantly inhibit xcex2-glucuronidase, and that certain other components of conventional formula upregulate the production of xcex2-glucuronidase. The supplementation of human breast milk with L-aspartic acid, but without other formula components that upregulate the production of xcex2-glucuronidase, decreases the circulation of bilirubin in neonates, and hence is designed to reduce the frequency of jaundice in such neonates.
Important is the discovery of the mechanism of interaction of L-aspartic acid and L-malic acid with the body. The finding of xcex2-glucuronidase inhibition enables the inventors to design and optimize a supplement for breast feeding neonates.
As such, the invention provides a method of administering a dietary supplement to a human infant that has at least in part been breast fed (preferably a newborn that is less than a month old). One administers to the infant a carrier mixed with L-aspartic acid and/or L-malic acid. The supplement does not contain any amino acids which stimulate xcex2-glucuronidase activity under the xe2x80x9cStandard Testxe2x80x9d conditions specified below.
In preferred forms the infant is less than two days old at the time of the administration, the carrier is human breast milk or water, and the administration is oral feeding. Through the use of this method xcex2-glucuronidase activity in the infant is inhibited and serum bilirubin levels can be reduced.
In another aspect the invention provides an infant formula containing breast milk and L-aspartic acid, L-malic acid, or mixtures thereof. The amino acid is at least in part exogenously supplied to the breast milk, in addition lo such L-aspartic acid and L-malic acid (if any) as the breast milk may naturally have.
In still another aspect the invention provides an infant formula containing a mix of at least seven amino acids, at least one of which is either L-aspartic acid or L-malic acid. The formula does not contain any amino acids which stimulate xcex2-glucuronidase in the Standard Test described below.
In yet another form the invention provides an infant formula containing a plurality of amino acids derived via hydrolysis of casein, and L-aspartic acid and/or L-malic acid which is not derived from hydrolysis of casein (regardless of whether L-aspartic acid and/or L-malic acid from hydrolysis of casein is also present). Again, the formula does not contain any amino acids which stimulate xcex2-glucuronidase in the Standard Test described below.
The invention can also provide a dietary supplement for an infant which is a fruit or vegetable juice mixed with L-aspartic acid and/or L-malic acid which is not derived from fruit or vegetable juice.
The advantages of the present invention therefore include providing:
(a) compounds of the above kind which can be used as supplements during breast-feeding;
(b) compounds of the above kind which help reduce serum bilirubin levels; and
(c) methods for using such compounds.